Method of making particles for use in a pharmaceutical composition

ABSTRACT

The invention relates to a method for making composite active particles for use in a pharmaceutical composition for pulmonary administration, the method comprising a milling step in which particles of active material are milled in the presence of particles of an additive material which is suitable for the promotion of the dispersal of the composite active particles upon actuation of an inhaler. The invention also relates to compositions for inhalation prepared by the method.

The present invention relates to particles and to methods of makingparticles. In particular, the invention relates to methods of makingcomposite active particles comprising a pharmaceutically active materialfor inhalation.

It is known to administer to patients drugs in the form of fineparticles (active particles). For example, in pulmonary administration aparticulate medicament composition is inhaled by the patient. Pulmonaryadministration is particularly suitable for medicaments which areintended to cure or alleviate respiratory conditions such as asthma andfor medicaments which are not suitable for oral ingestion such ascertain biological macromolecules. Known devices for the administrationof drugs to the respiratory system include pressurised metered doseinhalers (pMDI's) and dry powder inhalers (DPI's).

The size of the active particles is of great importance in determiningthe site of the absorption. In order that the particles be carried deepinto the lungs, the particles must be very fine, for example having amass median aerodynamic diameter of less than 10 μm. Particles havingaerodynamic diameters greater than 10 μm are likely to impact the wallsof the throat and generally do not reach the lung. Particles havingaerodynamic diameters in the range of 5 μm to 0.5 μm to will generallybe deposited in the respiratory bronchioles whereas smaller particleshaving aerodynamic diameters in the range of 2 to 0.05 μm are likely tobe deposited in the alveoli.

Such small particles are, however, thermodynamically unstable due totheir high surface area to volume ratio, which provides significantexcess surface free energy and encourages particles to agglomerate. Inthe inhaler, agglomeration of small particles and adherence of particlesto the walls of the inhaler are problems that result in the activeparticles leaving the inhaler as large agglomerates or being unable toleave the inhaler and remaining adhered to the interior of the inhaler.

In an attempt to improve that situation, dry powders for use in drypowder inhalers often include particles of an excipient material mixedwith the fine particles of active material. Such particles of excipientmaterial may be coarse, for example, having mass median aerodynamicdiameters greater than 90 μm, (such coarse particles are referred to ascarrier particles) or they may be fine.

The step of dispersing the active particles from other active particlesand from particles of excipient material, if present, to form an aerosolof fine active particles for inhalation is significant in determiningthe proportion of the dose of active material which reaches the desiredsite of absorption in the lungs. In order to improve the efficiency ofthat dispersal it is known to include in the composition additivematerials. Such additive materials are thought to reduce the attractiveforces between the particles thereby promoting their dispersal.Compositions comprising fine active particles and additive materials aredisclosed in WO 97/03649.

Fine particles of active material suitable for pulmonary administrationhave often been prepared by milling, for example, jet milling. However,once the particles reach a minimum size referred to as the criticalsize, they re-combine at the same rate as being fractured, or do notfracture effectively and therefore do not reduce further in size. Thus,manufacture of fine particles by milling can require much effort andthere are factors which consequently place limits on the minimum size ofparticles of active material which can be achieved, in practice, by suchmilling processes.

The present invention provides in a first aspect a method for makingcomposite active particles for use in a pharmaceutical composition forpulmonary administration, the method comprising a milling step in whichparticles of active material are milled in the presence of particles ofan additive material which is suitable for the promotion of thedispersal of the composite active particles upon actuation of aninhaler.

The method of the invention will, in general, produce composite activeparticles. The composite active particles are very fine particles ofactive material which have, upon their surfaces, an amount of theadditive material. The additive material is preferably in the form of acoating on the surfaces of the particles of active material. The coatingmay be a discontinuous coating. The additive material may be in the formof particles adhering to the surfaces of the particles of activematerial. As explained below, at least some of the composite activeparticles may be in the form of agglomerates.

When the composite active particles are included in a pharmaceuticalcomposition the additive material promotes the dispersal of thecomposite active particles on administration of that composition to apatient, via actuation of an inhaler. (“Actuation of an inhaler” refersto the process during which a dose of the powder is removed from itsrest position in the inhaler. That step takes place after the powder hasbeen loaded into the inhaler ready for use.) The effectiveness of thatpromotion of dispersal has been found to be enhanced in comparison to acomposition made by simple blending of similarly sized particles ofactive material with additive material.

The presence of the additive material on the surfaces of the particlesof active material may confer controlled or delayed release propertiesand may provide a barrier to moisture.

It has also been found that the milling of the particles of activematerial in the presence of an additive material produces significantlysmaller particles and/or requires less time and less energy than theequivalent process carried out in the absence of the additive material.Using the method of the invention, it has been possible to producecomposite active particles which have a mass median aerodynamic diameter(MMAD) or a volume median diameter (VMD) of less than 1 μm. It is oftennot possible to make such small particles by other milling methods.

It is known that a milling process will tend to generate and increasethe level of amorphous material on the surfaces of the milled particlesthereby making them more cohesive. In contrast, the composite activeparticles of the invention will often be found to be less cohesive afterthe milling treatment.

The word “milling” as used herein refers to any mechanical process whichapplies sufficient force to the particles of active material that it iscapable of breaking coarse particles (for example, particles of massmedium aerodynamic diameter greater than 100 μm) down to fine particlesof mass median aerodynamic diameter not more than 50 μm or which appliesa relatively controlled compressive force as described below in relationto the MECHANO-FUSION™ and CYCLOMIX™ methods. It has been found thatprocesses such as blending which do not apply a high degree of force arenot effective in the method of the invention. It is believed that isbecause a high degree of force is required to separate the individualparticles of active material and to break up tightly bound agglomeratesof the active particles such that effective mixing and effectiveapplication of the additive material to the surfaces of those particlesis achieved. It is believed that an especially desirable aspect of themilling process is that the additive material may become deformed in themilling and may be smeared over or fused to the surfaces of the activeparticles. It should be understood, however, that in the case where theparticles of active material are already fine, for example, having amass median aerodynamic diameter below 20 μm prior to the milling step,the size of those particles may not be significantly reduced. Theimportant thing is that the milling process applies a sufficiently highdegree of force or energy the particles.

The method of the invention generally involves bringing the additiveparticles into close contact with the surfaces of the active particles.In order to achieve coated particles, a degree of intensive mixing isrequired to ensure a sufficient break-up of agglomerates of bothconstituents, dispersal and even distribution of additive over the hostactive particles.

Where the additive particles are very small (typically <1 micron),generally less work is required, firstly as it is not required to breakor deform but only to deagglomerate, distribute and embed the additiveparticles onto the active particle and secondly because of the naturallyhigh surface energies of such small additive particles. It is known thatwhere two powder components are mixed and the two components differ insize, there is a tendency for the small particles to adhere to the largeparticles (to form so called ‘ordered mixes’). The short range Van derWaals interactions for such very fine components may be sufficient toensure adhesion. However, where both additive and active particles arevery fine (for example less than 5 microns) a substantial degree ofmixing will be required to ensure a sufficient break-up of agglomeratesof both constituents, dispersal and even distribution of additiveparticles over the active particles as noted above. In some cases asimple contact adhesion may be insufficient and a stronger embedding orfusion of additive particles onto active particles is required toprevent segregation, or to enhance the structure and functionality ofthe coating.

Where the additive particles are not so small as to be sufficientlyadhered by Van der Waals forces alone, or where there are advantages todistorting and/or embedding the additive particles substantially ontothe host active particle, a greater degree of energy is required fromthe milling. In this case, the additive particles should experiencesufficient force to soften and/or break, to distort and to flatten them.These processes are enhanced by the presence of the relatively harderactive particles which act as a milling media as well as ade-agglomerating media for such processes. As a consequence of thisprocess the additive particles may become wrapped around the core activeparticle to form a coating. These processes are also enhanced by theapplication of a compressive force as mentioned above.

As a consequence of the milling step, complete or partial, continuous ordiscontinuous, porous or non-porous coatings may be formed. The coatingsoriginate from a combination of active and additive particles. They arenot coatings such as those formed by wet processes that requiredissolution of one or both components. In general, such wet coatingprocesses are likely to be more costly and more time consuming than themilling process of the invention and also suffer from the disadvantagethat it is less easy to control the location and structure of thecoating.

A wide range of milling devices and conditions are suitable for use inthe method of the invention. The milling conditions, for example,intensity of milling and duration, should be selected to provide therequired degree of force. Ball milling is a preferred method.Centrifugal and planetary ball milling are especially preferred methods.Alternatively, a high pressure homogeniser may be used in which a fluidcontaining the particles is forced through a valve at high pressureproducing conditions of high shear and turbulence. Shear forces on theparticles, impacts between the particles and machine surfaces or otherparticles and cavitation due to acceleration of the fluid may allcontribute to the fracture of the particles and may also provide acompressive force. Such homogenisers may be more suitable than ballmills for use in large scale preparations of the composite activeparticles. Suitable homogenisers include EmulsiFlex® high pressurehomogenisers which are capable of pressures up to 4000 Bar, Niro Soavihigh pressure homogenisers (capable of pressures up to 2000 Bar), andMicrofluidics Microfluidisers (maximum pressure 2750 Bar). The millingstep may, alternatively, involve a high energy media mill or an agitatorbead mill, for example, the Netzch high energy media mill, or theDYNO-mill (Willy A. Bachofen A G, Switzerland). Alternatively themilling may be a dry coating high energy process such as aMechano-Fusion system (Hosokawa Micron Ltd) or a Hybridizer (Nara).Other possible milling devices include air jet mills, pin mills, hammermills, knife mills, ultracentrifugal mills and pestle and mortar mills.

Especially preferred methods are those involving the MECHANO-FUSION™,Hybridiser and CYCLOMIX™ instruments.

Preferably, the milling step involves the compression of the mixture ofactive and additive particles in a gap (or nip) of fixed, predeterminedwidth (for example, as in the MECHANO-FUSION™ and CYCLOMIX™ methodsdescribed below).

Some preferred milling methods will now be described in greater detail.

MECHANO-FUSION™:

As the name suggests, this dry coating process is designed tomechanically fuse a first material onto a second material. The firstmaterial is generally smaller and/or softer than the second. TheMECHANO-FUSION™ and CYCLOMIX™ working principles are distinct fromalternative milling techniques in having a particular interactionbetween inner element and vessel wall, and are based on providing energyby a controlled and substantial compressive force.

The fine active particles and the additive particles are fed into theMECHANO-FUSION™ driven vessel, where they are subject to a centrifugalforce and are pressed against the vessel inner wall. The powder iscompressed between the fixed clearance of the drum wall and a curvedinner element with high relative speed between drum and element. Theinner wall and the curved element together form a gap or nip in whichthe particles are pressed together. As a result the particles experiencevery high shear forces and very strong compressive stresses as they aretrapped between the inner drum wall and the inner element (which has agreater curvature than the inner drum wall). The particles violentlycollide against each other with enough energy to locally heat andsoften, break, distort, flatten and wrap the additive particles aroundthe core particle to form a coating. The energy is generally sufficientto break up agglomerates and some degree of size reduction of bothcomponents may occur. Embedding and fusion of additive particles ontothe active particles may occur, and may be facilitated by the relativedifferences in hardness (and optionally size) of the two components.Either the outer vessel or the inner element may rotate to provide therelative movement. The gap between these surfaces is relatively small,and is typically less than 10 mm and is preferably less than 5 mm, morepreferably less than 3 mm. This gap is fixed, and consequently leads toa better control of the compressive energy than is provided in someother forms of mill such as ball and media mills. Also, in general, noimpaction of milling media surfaces is present so that wear andconsequently contamination are minimised. The speed of rotation may bein the range of 200 to 10,000 rpm. A scraper may also be present tobreak up any caked material building up on the vessel surface. This isparticularly advantageous when using fine cohesive starting materials.The local temperature may be controlled by use of a heating/coolingjacked built into the drum vessel walls. The powder may be re-circulatedthrough the vessel.

CYCLOMIX™ Method (Hosokawa Micron):

The CYCLOMIX™ comprises a stationary conical vessel with a fast rotatingshaft with paddles which move close to the wall. Due to the highrotational speed of the paddles, the powder is propelled towards thewall, and as a result the mixture experiences very high shear forces andcompressive stresses between wall and paddle. Such effects are similarto the MECHANO-FUSION™ as described above and may be sufficient tolocally heat and soften, to break, distort, flatten and wrap theadditive particles around the active particles to form a coating. Theenergy is sufficient to break up agglomerates and some degree of sizereduction of both components may also occur depending on the conditionsand upon the size and nature of the particles.

This is a dry process which can be described as a product embedding orfilming of one powder onto another. The fine active particles and fineor ultra fine additive particles are fed into a conventional high shearmixer pre-mix system to form an ordered mixture. This powder is then fedinto the Hybridiser. The powder is subjected to ultra-high speed impact,compression and shear as it is impacted by blades on a high speed rotorinside a stator vessel, and is re-circulated within the vessel. Theactive and additive particles collide with each other. Typical speeds ofrotation are in the range of 5,000 to 20,000rpm. The relatively softfine additive particles experience sufficient impact force to soften,break, distort, flatten and wrap around the active particle to form acoating. There may also be some degree of embedding into the surface ofthe active particles.

Other preferred methods include ball and high energy media mills whichare also capable of providing the desired high shear force andcompressive stresses between surfaces, although as the clearance gap isnot controlled, the coating process may be less well controlled than forMECHANO-FUSION™ milling and some problems such as a degree of undesiredre-agglomeration may occur. These media mills may be rotational,vibrational, agitational, centrifugal or planetary in nature.

It has been observed in some cases that when ball milling activeparticles with additive material, a fine powder is not produced. Insteadthe powder was compacted on the walls of the mill by the action of themill. That has inhibited the milling action and prevented thepreparation of the composite active particles. That problem occurredparticularly when certain additive materials were used, in cases wherethe additive material was present in small proportions (typically <2%),in cases where the milling balls were relatively small (typically <3mm), in cases where the milling speed was too slow and where thestarting particles were too fine. To prevent this occurring it isadvantageous to ball mill in a liquid medium. The liquid medium reducesthe tendency to compaction, assists the dispersal of additive materialand improves any milling action.

It has been found to be preferable to use a large number of fine millingballs, rather than fewer heavy balls. The finer balls perform a moreefficient co-milling action. Preferably the balls have a diameter ofless than 5 mm, advantageously less than 2 mm. Liquid media arepreferred which do not dissolve the active material and which evaporaterapidly and fully, for example non-aqueous liquids such as diethylether,acetone, cyclohexane, ethanol, isopropanol or dichloromethane. Liquidmedia are preferred which are non flammable, for example dichloromethaneand fluorinated hydrocarbons, especially fluorinated hydrocarbons whichare suitable for use as propellants in inhalers.

Pestle and mortar mills are other mills which also provide a very highshear force and compressive stresses between surfaces.

Mechano-Micros and Micros mills made by Nara (where particles arecompressed by rotating grinding rings) may also be used. Mills referredto impact mixers, attrition mills, pin mills and disc mills may also beused.

The mass median aerodynamic diameter of the particles of active materialmay be substantially reduced during the milling step especially when theactive material is in the form of coarse particles prior to the millingstep. The mass median aerodynamic diameter (MMAD) of the particles ofactive material may be reduced by at least 10%, by at least 50%, or byat least 70% during the milling step depending on the milling conditionsand the MMAD of the active particles prior to the milling step.

Advantageously, after the milling step, the MMAD of the active particlesis less than 9 μm, preferably less then than 4 μm and more preferablyless than 2 μm.

In a similar way, where the additive material is in the form of coarseparticles prior to the milling step, their MMAD will be substantiallyreduced during the milling step. The MMAD of the particles of additivematerial may be reduced by at least 10%, at least 50% or at least 70%during the milling step, depending on the milling conditions and on theMMAD of the particles of additive material before the milling step. Thesize of the additive particles after the milling step is preferablysignificantly less than the size of the active particles, to enable theadditive materials to more effectively coat the surfaces of the activeparticles. In practice, that difference in size between the activeparticles and additive particles is likely to be achieved as aconsequence of the milling because the additive material will usually bemore easily fractured or deformed than the active material and so willbe broken into smaller particles than the active material. As notedabove, the particles of additive material preferably become smeared overor fused to the surfaces of the particles of active material, therebyforming a coating which may be substantially continuous ordiscontinuous. Where the coating is discontinuous, it preferably covers,on average, at least 50% (that is, at least 50% of the total surfacearea of the active particles will be covered by additive material), moreadvantageously at least 70% and most preferably at least 90% of thesurfaces of the active particles. The coating is preferably on averageless than 1 μm, more preferably less than 0.5 μm and most preferablyless than 200 nm thick.

The milling step may be carried out in a closed vessel, for example in aball mill or a Mechano-Fusion device. The use of a closed vesselprevents loss of ultrafine particles or vapour of the additive materialwhich has been found to occur in jet milling or other open processes.Preferably, the milling is not jet milling (micronisation).

The milling may be wet milling, that is, the milling step may be carriedout in the presence of a liquid. That liquid medium may be high or lowvolatility and of any solid content as long as it does not dissolve theactive particles to any significant degree and its viscosity is not sohigh that it prevents effective milling. The liquid medium preferably isnot aqueous. The liquid is preferably one in which the additive materialis substantially insoluble but some degree of solubility may beacceptable as long as there is sufficient additive material present thatundissolved particles of additive material remain. The presence of aliquid medium helps to prevent compacting of the particles of activematerial on the walls of the vessel and may also allow the more evenspreading of the additive material on the surface of the particles ofactive material as compared to dry milling.

It has been found that the Mechano-Fusion and Cyclomix techniquesreferred to above often provide the composite active particles asindividual, that is, unagglomerated composite active particles. That isin contrast to less controlled methods such as ball milling, which havebeen found to often produce the composite active particles in the formof agglomerated composite active particles.

The mass median aerodynamic diameter of the composite active particlesis preferably not more than 10 μm, and advantageously it is not morethan 5 μm, more preferably not more than 3 μm and most preferably notmore than 1 μm. Accordingly, advantageously at least 90% by weight ofthe composite active particles have a diameter of not more than 10 μm,advantageously not more than 5 μm, preferably not more than 3 μm andmore preferably not more than 1 μm. Advantageously, after the millingstep, the active particles will be of a suitable size for inhalation tothe desired part of the lung, for example, having an MMAD in the rangeof 3 to 0.1 μm for absorption in the deep lung, 5 to 0.5 μm forabsorption in the respiratory bronchioles, 10 to 2 μm for delivery tothe higher respiratory system and 2 to 0.05 μm for delivery to thealveoli. Accordingly, advantageously the diameter of at least 90% byweight of the composite active particles have an aerodynamic diameter inthe range of 3 to 0.1 μm, preferably 5 to 0.5 μm, advantageously 10 to 2μm, and especially advantageously 2 to 0.05 μm. The MMAD of the activeparticles will not normally be lower than 0.01 μm. p As mentioned above,the composite active particles produced after the milling step may be ofa suitable size for delivery to the desired part of the respiratorysystem.

However, the composite active particles may be smaller than thatsuitable size or at least some of the composite active particles may,after the milling step, be in the form of agglomerates which are largerthan the suitable size. The method therefore preferably also comprises,after the milling step, a processing step in which the degree ofagglomeration of the composite active particles is changed. Theprocessing step may be an agglomeration step in which the particles ofactive material agglomerate to form agglomerated composite activeparticles. In that way agglomerates of a size tailored to therequirement may be produced. Whilst any method of agglomeration can beused, for example, granulation, preferably, the composite activeparticles are agglomerated in a drying step (as described below) to formagglomerated composite active particles. Preferably, the agglomerationstep is a spray drying step. The spray drying conditions may be selectedto produce droplets having a desired size in the range of 1000 μm to 0.5μm. The size of the agglomerates produced will depend largely on theconcentration of the composite active particles in the spray feed andthe droplet size. Other materials, for example, binders may be includedin the spray feed. Where the milling step involves wet milling, thesuspension or slurry may be spray dried directly after the milling step.Agglomeration may also be conducted in a fluid bed dryer or granulator.

Where, after the milling step, at least some of the composite activeparticles are in the form of agglomerates and it is desired to breakthose agglomerates down or to reduce their size, the processing step maybe a deagglomeration step. The deagglomeration step may involvemechanical breaking up of the unwanted agglomerates, for example, byforcing them through a sieve or by subjecting them to a treatment in adry fluidised bed, a jet mill, a ball mill or other form of millingdevice. The intensity and/or duration of that treatment step will, ingeneral, be less that of the milling step. The deagglomeration step mayalso be a spray drying step because, whilst spray drying as a dryingstep is particularly useful in preparing agglomerated composite activeparticles, by appropriate control of the conditions it is possible toproduce the composite active particles largely as single particlesrather than as agglomerates.

The term “agglomerated composite active particles” refers to particleswhich consist of more than one composite active particle, thosecomposite active particles being adhered to each other. Where theagglomerated particles are for inhalation they will preferably have aMMAD which renders them suitable for deposition in the desired part ofthe lung.

Preferably, the method comprises, after the milling step, a drying stepin which a mixture of the composite active particles and a liquid isdried to remove the liquid. The mixture may be in the form of a slurryor suspension. During the drying step, especially when spray drying isused, the degree of agglomeration of the composite active particles maychange, in which case the drying step is the same step as the processingstep mentioned above. However, the drying step may be included for otherreasons, for example, when the milling is wet milling, and it is desiredto produce the composite active particles as a dry powder.

The drying step may involve filtration followed by drying, orevaporation of the liquid. Preferably, the drying step is a spray dryingstep. Alternatively, the liquid may be evaporated slowly or the dryingstep may be a freeze drying step.

The milling is preferably dry, that is to say, there is no liquidpresent during the milling and the mixture to be milled is in the formof a dry particulate. In that case, liquid may be added after themilling step, usually in order that a drying step be used to formagglomerated composite active particles, as described above.

Advantageously, the milling step is carried out at a reducedtemperature, for example, below 10° C. and preferably below 0° C. Suchlow temperature conditions may increase the efficiency of the millingstep and/or reduce decomposition of the active material.

The optimum amount of additive material will depend on the chemicalcomposition and other properties of the additive material and upon thenature of the active material and/or excipient material. In general, theamount of additive material in the composite particles will be not morethan 60% by weight, based on the weight of the active material and/orexcipient material. However, it is thought that for most additivematerials the amount of additive material should be in the range of 40%to 0.25%, preferably 30% to 0.5%, more preferably 20% to 2%, based onthe total weight of the additive material and the active material beingmilled. In general, the amount of additive material is at least 0.01% byweight based on the weight of the active material.

The terms “additive particles” and “particles of additive material” areused interchangeably herein. The additive particles comprise one or moreadditive materials. Preferably, the additive particles consistessentially of the additive material.

Advantageously the additive material is an anti-adherent material andwill tend to decrease the cohesion between the composite activeparticles and between the composite active particles and any otherparticles present in the pharmaceutical composition.

Advantageously the additive material is an anti-friction agent (glidant)and will give better flow of the pharmaceutical composition in, forexample, a dry powder inhaler which will lead to a better dosereproducibility.

Where reference is made to an anti-adherent material, or to ananti-friction agent, the reference is to include those materials whichare able to decrease the cohesion between the particles, or which willtend to improve the flow of powder in an inhaler, even though they maynot usually be referred to as anti-adherent material or an anti-frictionagent. For example, leucine is an anti-adherent material as hereindefined and is generally thought of as an anti-adherent material butlecithin is also an anti-adherent material as herein defined, eventhough it is not generally thought of as being anti-adherent, because itwill tend to decrease the cohesion between the composite activeparticles and between the composite active particles and any otherparticles present in the pharmaceutical composition.

The additive material may include a combination of one or morematerials.

It will be appreciated that the chemical composition of the additivematerial is of particular importance. Preferably, the additive materialis a naturally occurring animal or plant substance.

Advantageously, the additive material includes one or more compoundsselected from amino acids and derivatives thereof, and peptides andderivatives thereof. Amino acids, peptides and derivatives of peptidesare physiologically acceptable and give acceptable release of the activeparticles on inhalation.

It is particularly advantageous for the additive material to comprise anamino acid. The additive material may comprise one or more of any of thefollowing amino acids: leucine, isoleucine, lysine, valine, methionine,phenylalanine. The additive may be a salt or a derivative of an aminoacid, for example aspartame or acesulfame K. Preferably, the additiveparticles consist substantially of an amino acid, more preferably ofleucine, advantageously L-leucine. The D- and DL-forms may also be used.As indicated above, leucine has been found to give particularlyefficient dispersal of the active particles on inhalation.

The additive material may include one or more water soluble substances.This helps absorption of the substance by the body if the additivereaches the lower lung. The additive material may include dipolar ions,which may be zwitterions.

Alternatively, the additive material may comprise a phospholipid or aderivative thereof. Lecithin has been found to be a good material forthe additive material.

Preferably, the additive material comprises a metal stearate, or aderivative thereof, for example, sodium stearyl fumarate or sodiumstearyl lactylate. Advantageously, the additive material comprises ametal stearate. For example, zinc stearate, magnesium stearate, calciumstearate, sodium stearate or lithium stearate. Preferably, the additivematerial comprises magnesium stearate.

The additive material may include or consist of one or more surfaceactive materials, in particular materials that are surface active in thesolid state, which may be water soluble, for example lecithin, inparticular soya lecithin, or substantially water insoluble, for examplesolid state fatty acids such as oleic acid, lauric acid, palmitic acid,stearic acid, erucic acid, behenic acid, or derivatives (such as estersand salts) thereof such as glyceryl behenate. Specific examples of suchmaterials are: phosphatidylcholines, phosphatidylethanolamines,phosphatidylglycerols and other examples of natural and synthetic lungsurfactants; lauric acid and its salts, for example, sodium laurylsulphate, magnesium lauryl sulphate; triglycerides such as DYNASAN® 118and Cutina® HR; and sugar esters in general.

Other possible additive materials include sodium benzoate, hydrogenatedoils which are solid at room temperature, talc, titanium dioxide,aluminium dioxide, silicon dioxide and starch.

The additive material preferably comprises one or more materialsselected from the group consisting of amino acids, lecithins,phospholipids, sodium stearyl fumarate, glyceryl behenate and metalstearates (especially magnesium stearate).

The terms “active particles” and “particles of active material” are usedinterchangeably herein. The active particles referred to throughout thespecification will comprise one or more pharmacologically active agents.The active particles advantageously consist essentially of one or morepharmacologically active agents. Suitable pharmacologically activeagents may be materials for therapeutic and/or prophylactic use. Activeagents which may be included in the formulation include those productswhich are usually administered orally by inhalation for the treatment ofdisease such as respiratory disease, for example, β-agonists.

The active particles may comprise at least one β₂-agonist, for exampleone or more compounds selected from terbutaline, salbutamol, salmeteroland formetorol. If desired, the active particles may comprise more thanone of those active agents, provided that they are compatible with oneanother under conditions of storage and use. Preferably, the activeparticles are particles of salbutamol sulphate. References herein to anyactive agent is to be understood to include any physiologicallyacceptable derivative. In the case of the β₂-agonists mentioned above,physiologically acceptable derivatives include especially salts,including sulphates.

The active particles may be particles of ipatropium bromide.

The active particles may include a steroid, which may be beclomethasonedipropionate or may be fluticasone. The active principle may include acromone which may be sodium cromoglycate or nedocromil. The activeprinciple may include a leukotriene receptor antagonist.

The active particles may include a carbohydrate, for example heparin.

The active particles may advantageously comprise a pharmacologicallyactive agent for systemic use and advantageously they are capable ofbeing absorbed into the circulatory system via the lungs. For example,the active particles may comprise peptides or polypeptides such asDnase, leukotrienes or insulin. The pharmaceutical compositions of theinvention may in particular have application in the administration ofinsulin to diabetic patients, preferably avoiding the normally invasiveadministration techniques used for that agent. The composite activeparticles could also be used for the local administration of otheragents for example for pain relief (e.g. analgesics such as fentanyl ordihydroergotamine which is used for the treatment of migraine), anticancer activity, anti-virals, antibiotics or the local delivery ofvaccines to the respiratory tract.

Whilst it will often be desired to obtain the composite active particlesin dry form, as described above, where the pharmaceutical composition isone comprising a liquid, for example, as propellant, it may bepreferable for the active particles to be milled in the presence of thatliquid and to omit the drying step, simply using the slurry orsuspension of the composite active particles in the liquid as aningredient in the pharmaceutical composition. Thus for example, wherethe pharmaceutical composition is for use in a pMDI, the activeparticles and the additive material may be milled in the presence ofliquid propellant (under pressure or at below room temperature ifnecessary). The resulting slurry may be used directly in a pMDI orfurther materials may be added, for example, more propellant,surfactants, or co-solvents.

Accordingly, the invention also provides, in one embodiment, a method ofmaking composite active particles for use in a pharmaceuticalcomposition, the method comprising a milling step in which particles ofactive material are milled in the presence of a liquid and an additivematerial which is suitable for the promotion of the dispersal of thecomposite active particles upon actuation of a delivery device.

Preferably, the liquid comprises a propellant suitable for use in apMDI. Suitable propellants include CFC-12, HFA-134a, HFA-227, HCFC-22(difluorochlormethane), HCFC-123 (dicholorotrifluorethane), HCFC-124(chlorotetrafluoroethane), dimethyl ether, propane, n-butane, isobutane,HFA-125 (pentafluoroethane) and HFA-152 (difluoroethane). If however, itis desired to isolate the dry composite active particles (oragglomerates thereof) the method may also include a drying step,preferably a spray drying step. Accordingly, in a further embodiment,the invention provides a method of making composite active particles foruse in a pharmaceutical composition, the method comprising

a wet milling step in which the particles of active material are milledin the presence of a liquid and an additive material which is suitablefor the promotion of the dispersal of the composite active particlesupon actuation of a delivery device; and

a drying step in which the liquid is removed.

As explained above, the conditions of the drying step, which ispreferably a spray drying step, may be chosen either to provideagglomerated composite active particles of a desired size or to providesubstantially unagglomerated particles, that is, individual compositeactive particles. In some cases it may be preferable to perform themilling step in the absence of liquid, (dry milling). The compositeactive particles may then be agglomerated by mixing with a liquid anddrying to give agglomerated composite active particles. Accordingly, ina further embodiment, the invention provides a method of makingagglomerated composite active particles for use in a pharmaceuticalcomposition, the method comprising:

a dry milling step in which particles of active material are milled inthe presence of an additive material which is suitable for the promotionof the dispersal of the composite active particles upon actuation of adelivery device; and

an agglomeration step, in which the composite active particles are mixedwith a liquid and the mixture is dried to remove the liquid.

The invention also provides composite active particles for use in apharmaceutical composition, preferably a pharmaceutical composition forinhalation, more preferably a powder for a dry powder inhaler.

The invention also provides composite active particles for use in apharmaceutical composition, each composite active particle comprising aparticle of active material and additive material on the surface of thatparticle of active material, the composite active particles having amass median aerodynamic diameter of not more than 2 μm, the additivematerial being suitable for the promotion of the dispersal of thecomposite active particles upon actuation of a delivery device.Preferably, the composite active particles have a MMAD of not more than1 μm, especially advantageously not more than 0.5 μm. As noted above,the composite particles may be in the form of agglomerated compositeparticles.

MMAD may be determined using an impinger, for example, a multi-stageliquid impinger. Volume median diameters and measurements of theproportion of particles having a diameter less than a certain value maybe determined by the Malvern laser light scattering method.

Advantageously, the composite active particles do not comprisesignificant amounts (more then 10% by weight) of a polymer of a typewhich would result in the particles becoming sticky. Such polymersinclude polymers of a alpha-hydroxycarboxylic acid, for example,polylactic acid, copolymers of lactic acid and block copolymers such asethylene oxide/propylene oxide block copolymers or poloxamines.

The invention further provides a pharmaceutical composition comprisingcomposite active particles. Preferably, the pharmaceutical compositionis a dry powder and is suitable for use in a dry powder inhaler. Suchpharmaceutical compositions may comprise essentially only the compositeactive particles or they may comprise additional ingredients such ascarrier particles and flavouring agents. Carrier particles may be of anyacceptable excipient material or combination of materials. For example,the carrier particles may be composed of one or more materials selectedfrom sugar alcohols, polyols and crystalline sugars. Other suitablecarriers include inorganic salts such as sodium chloride and calciumcarbonate, organic salts such as sodium lactate and other organiccompounds such as polysaccharides and oligosaccharides. Advantageouslythe carrier particles are of a polyol. In particular the carrierparticles may be particles of crystalline sugar, for example mannitol,dextrose or lactose. Preferably, the carrier particles are of lactose.

Advantageously, substantially all (by weight) of the carrier particleshave a diameter which lies between 20 μm and 1000 μm, more preferably 50μm and 1000 μm. Preferably, the diameter of substantially all (byweight) of the carrier particles is less than 355 μm and lies between 20μm and 250 μm. Preferably at least 90% by weight of the carrierparticles have a diameter between from 60 μm to 180 μm. The relativelylarge diameter of the carrier particles improves the opportunity forother, smaller particles to become attached to the surfaces of thecarrier particles and to provide good flow and entrainmentcharacteristics and improved release of the active particles in theairways to increase deposition of the active particles in the lowerlung.

The ratio in which the carrier particles (if present) and compositeactive particles are mixed will, of course, depend on the type ofinhaler device used, the type of active particles used and the requireddose. The carrier particles may be present in an amount of at least 50%,more preferably 70%, advantageously 90% and most preferably 95% based onthe combined weight of the composite active particles and the carrierparticles.

Where carrier particles are included in the pharmaceutical composition,that composition preferably also includes small excipient particleshaving, for example, a particle size between 5 to 20 μm. Preferably thesmall excipient particles are present in an amount of from 1% to 40%,more preferably 5% to 20% based on the weight of the carrier particles.

Compositions for use in a dry powder inhaler which include carrierparticles will preferably include at least 2%, more preferably at least5% and most preferably at least 10% by weight of the composite activeparticles based on the total mass of the composition. The compositeactive particles are especially suitable for dry powder compositionswhich do not include significant amounts of carrier particles and insuch compositions the composite active particles will preferably bepresent in a proportion of at least 60%, more preferably at least 80% byweight based on the total weight of the composition.

The pharmaceutical composition may comprise a propellant and be suitablefor use in a pressurised metered dose inhaler.

The invention also provides the use of an additive material as a millingaid in the milling of particles of active material. The term milling aidshould be understood to refer to a substance which reduces the amount ofenergy required to mill the particles of active material and/orexcipient material.

Embodiments of the invention will now be described for the purposes ofillustration only with reference to the Figures in which:

FIGS. 1 and 2 are scanning electron micrographs of the composite activeparticles of Example 1;

FIG. 3 is a scanning electron micrograph of the composite activeparticles of Example 1a;

FIG. 4 is a scanning electron micrograph of the composite particles ofExample 2;

FIG. 5 is a scanning electron micrograph of the same sample of particlesshown in FIG. 4 but at a higher magnification;

FIG. 6 is a scanning electron micrograph of the composite particles ofExample 3;

FIG. 7 is a scanning electron micrograph of the same sample of particlesshown in FIG. 6 but at a higher magnification;

FIG. 8 is a schematic drawing of part of a Mechano-Fusion machine; and

FIGS. 9 and 10 are electromicrographs of composite active particlesaccording to the invention comprising salbutamol sulphate and magnesiumstearate in a ratio of 19:1 (Example 4).

All percentages are by weight unless indicated otherwise.

EXAMPLE 1

5 g of micronised salbutamol sulphate (particle size distribution: 1 to5 μm) and 0.5 g of magnesium stearate were added to a 50 cm³ stainlesssteel milling vessel together with 20 cm³ dichloromethane and 124 g of 3mm stainless steel balls. The mixture was milled at 550 rpm in a RetschS100 Centrifugal Mill for 5 hours. The powder was recovered by dryingand sieving to remove the mill balls. An electron micrograph of thepowder is shown in FIG. 1. This was repeated 3 times using leucine inplace of the magnesium stearate and an electron micrograph of the powderis shown in FIG. 2. The powders shown in FIGS. 1 and 2 appear to haveparticles in the size range 0.1 to 0.5 μm.

EXAMPLE 1a

Micronised salbutamol sulphate and magnesium stearate were combined asparticles in a suspension in the ratio 10:1 in propanol. This suspensionwas processed in an EmulsiFlex° C50 high pressure homogeniser by 5sequential passes through the system at 25,000 psi. This dry materialwas then recovered by evaporating the propanol. The particles are shownin FIG. 3.

EXAMPLE 2

It was found that, on drying, the powder prepared in Example 1 includingmagnesium stearate as additive material formed assemblies of primaryparticles which were hard to deagglomerate. A sample of this powder wasre-dispersed by ball milling for 90 minutes at 550 rpm in a mixture ofethanol, polyvinylpyrolidone (PVPK30) and HFA227 liquid propellant togive the following composition:

0.6% w/w Salbutamol sulphate/magnesium stearate composite particles 0.2%w/w PVPK30 5.0% w/w Ethanol 94.2% w/w HFA 227

(The PVP was included to stabilise the suspension of the compositeparticles in the ethanol/HFA227).

The suspension could be used directly as in a pMDI. In this example,however, the composition was sprayed from a pressurised can through anorifice about ˜0.4 mm in diameter to produce dried composite activeparticles of salbutamol sulphate and magnesium stearate with PVP. Thoseparticles (shown in FIGS. 4 and 5) were collected and examined and werefound to be in the aerodynamic size range 0.1 to 4 μm.

EXAMPLE 3

The process of Example 2 was repeated except that the composition was asfollows:

3% w/w Salbutamol sulphate/magnesium stearate composite particles 1% w/wPVPK30 3% w/w Ethanol 93% w/w HFA 227

The particles produced are shown in FIGS. 6 and 7.

EXAMPLE 4 Salbutamol Sulphate/Magnesium Stearate Blends

a) Homogenised Magnesium Stearate 240 g magnesium stearate (Riedel deHaen, particle size by Malvern laser diffraction: d₅₀=9.7 μm) wassuspended in 2150 g dichloroethane. That suspension was then mixed for 5minutes in a Silverson high shear mixer. The suspension was thenprocessed in an EmulsiFlex® C50 high pressure homogeniser fitted with aheat exchanger at 10000 psi for 20 minutes in circulation mode (300cm³/min) for 20 minutes. The suspension was then circulated atatmospheric pressure for 20 minutes allow it to cool. The next day, thesuspension was processed in circulation mode (260 cm³/min) at 20000 psifor 30 minutes. The dichloroethane was removed by rotary evaporationfollowed by drying in a vacuum over at 37° C. overnight. The resultingcake of material was broken up by ball milling for 1 minute. Thehomogenised magnesium stearate had a particle size of less than 2 μm.

A 9:1 by weight blend of salbutamol sulphate and homogenised magnesiumstearate having a particle size of less than 2 μm was prepared byblending the two materials with a spatula. An electron micrograph of theblended material showed that the blend was mostly in the form ofagglomerated particles, the agglomerates having diameters of 50 μm andabove. The blend was then processed in a MECHANO-FUSION™ mill (Hosokawa)as follows:

Machine data: Hosokawa Mechano-Fusion: AMS-Mini Drive: 2.2 kW Housing:stainless steel Rotor: stainless steel Scraper: None Cooling: Water Gaspurge: None

The MECHANO-FUSION™ device (see FIG. 8) comprises a cylindrical drum 1having an inner wall 2 In use, the drum rotates at high speed. Thepowder 3 of the active and additive particles is thrown by centrifugalforce against the inner wall 2 of the drum 1. A fixed arm 4 projectsfrom the interior of the drum in a radial direction. At the end of thearm closest to the wall 2, the arm is provided with a member 5 whichpresents an arcuate surface 6, of radius of curvature less than that ofinner wall 2, toward that inner wall. As the drum 1 rotates, it carriespowder 3 into the gap between arcuate surface 6 and inner wall 2 therebycompressing the powder. The gap is of a fixed, predetermined width A. Ascraper (not shown in FIG. 8) may be provided to scrape the compressedpowder from the wall of the drum.

All samples were premixed for 5 minutes by running the machine at 1000rpm. The machine speed was then increased to 5050 rpm for 30 minutes.The procedure was repeated for salbutamol sulphate/magnesium stearate inthe following weight ratios: 19:1, 3:1, 1:1.

Electronmicrographs of the 19:1 processed material are shown in FIGS. 9and 10 and indicate that the material was mostly in the form of simplesmall particles of diameter less than 5 μm or in very loose agglomeratesof such particles with only one agglomerate of the original type beingvisible.

The 3:1 and the 19:1 blends were then each loaded into a 20 mg capsuleand fired from a twin stage impinger. A sample of unprocessed salbutamolsulphate was also fired from the TSI to provide a comparison.

The fine particle fractions were then calculated and are given in table1.

TABLE 1 Fine Particle Fraction results for salbutamol sulphate blends.Composition Fine Particle Fraction % salbutamol sulphate 28 salbutamolsulphate/magnesium 66 stearate 19:1 salbutamol sulphate/magnesium 66stearate 3:1

EXAMPLE 5

Micronised glycopyrrolate and homogenised magnesium stearate (asdescribed in Example 4) were combined in a weight ratio of 75:25. Thisblend (˜20 g) was then milled in the MECHANO-FUSION™ AMS-Mini system asfollows. The powder was pre-mixed for 5 minutes at ˜900 rpm. The machinespeed was then increased to ˜4,800 rpm for 30 minutes. During themilling treatment the MECHANO-FUSION™ machine was run with a 3 mmclearance between element and vessel wall, and with cooling waterapplied. The powder of composite active particles was then recoveredfrom the drum vessel.

The experiment was repeated using the same procedure but the activeparticle and homogenised magnesium stearate were combined in the ratio95:5, and milled for 60 minutes at 4,800 rpm.

This above process was repeated using the same procedure with a sampleof sodium salicilate as a model drug and homogenised magnesium stearatein the ratio 90:10, where the sodium salicilate had been produced asapproximately micron sized spheres by spray drying from a Buchi 191spray dryer. It was believed that the spherical shape of these particlesmay be advantageous in the coating process. Milling was for 30 minutesat 4,800 rpm.

1. A method for making composite active particles for use in apharmaceutical composition for pulmonary administration, the methodcomprising a milling step in which particles of active material aremilled in the presence of particles of an additive material so as toensure a sufficient break-up of agglomerates of both active material andadditive material, dispersal and even distribution of the additivematerial over the active material, and so that the particles of additivematerial become fused to the surface of the particles of activematerial; wherein the additive material is suitable for the promotion ofthe dispersal of the composite active particles upon actuation of aninhaler, wherein the milling step comprises: (a) passing a mixture ofparticles of additive material and particles of active material, in afluid, through a constriction under pressure; (b) compressing a mixtureof particles of additive material and particles of active material in agap of predetermined width; or (c) jet milling particles of additivematerial with particles of active material to provide a break-up ofagglomerates of both active material and additive material, dispersaland distribution of the additive material over the active material, suchthat the particles of additive material become fused to the surface ofthe particles of active material, wherein the additive material issuitable for the promotion of the dispersal of the composite activeparticles upon actuation of an inhaler.
 2. A method as claimed in claim1, in which the mass median aerodynamic diameter (MMAD) of the particlesof active material is reduced by at least 10% during the milling step.3. A method as claimed in claim 1, in which the mass median aerodynamicdiameter (MMAD) of the particles of additive material is reduced by atleast 10% during the milling step.
 4. A method as claimed in claim 1, inwhich, after the milling step, the mass median aerodynamic diameter ofthe composite active particles is not more than 10 μm.
 5. A method asclaimed in claim 1, which also comprises, after the milling step, aprocessing step in which the degree of aggregation of the compositeactive particles is changed.
 6. A method as claimed in claim 5, in whichthe processing step is a deagglomeration step.
 7. A method as claimed inclaim 1, wherein after the milling step, liquid is added, followed by adrying step in which the mixture of the composite active particles andthe liquid is dried to remove the liquid.
 8. A method as claimed inclaim 7, in which the drying step is a spray drying step.
 9. A method asclaimed in claim 7, in which in the drying step the liquid isevaporated.
 10. A method as claimed in claim 7, in which the drying stepis a freeze drying step.
 11. A method as claimed in claim 1, in whichthe additive material comprises an amino acid.
 12. A method as claimedin claim 1, in which the additive material comprises a phospholipid. 13.A method as claimed in claim 1, in which the additive material comprisesa metal stearate.
 14. A method according to claim 1 in which the millingstep involves compressing a mixture of the active particles and additiveparticles in a gap not more than 10 mm wide.
 15. A method as claimed inclaim 1, in which the milling step is performed using a hybridisermethod.
 16. Composite active particles for use in a pharmaceuticalcomposition as made by the method of claim
 1. 17. Composite particles asclaimed in claim 16 in which the additive particles form a coating onthe surfaces of the particles of active material.
 18. Composite activeparticles as claimed in claim 17 in which the coating is a discontinuouscoating.
 19. Composite active particles as claimed in claim 17 in whichthe coating is not more than 1 μm thick.
 20. A pharmaceuticalcomposition comprising composite active particles as claimed in claim16, which is a dry powder and is suitable for use in a dry powderinhaler.
 21. A pharmaceutical composition comprising composite activeparticles as made by a method according to claim
 1. 22. A pharmaceuticalcomposition as claimed in claim 21, which further comprises a propellantand is suitable for use in a pressurized metered dose inhaler.